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Cited by 421

The DOI matches its Crossref record; 19 of the 19 references it cites were found in a registry or an index.

Phosphorylation of the Translation Initiation Factor eIF2α Increases BACE1 Levels and Promotes Amyloidogenesis

Open access
O'Connor, Tracy, Sadleir, Katherine R., Maus, Erika, Velliquette, Rodney A., Zhao, Jie, Cole, Sarah L., Eimer, William A., Hitt, Brian, Bembinster, Leslie A., Lammich, Sven, Lichtenthaler, Stefan F., Hébert, Sébastien S., De Strooper, Bart, Haass, Christian, Bennett, David A., Vassar, Robert·2008·Neuron
DOI 10.1016/j.neuron.2008.10.047
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Abstract

Summary Beta-site APP cleaving enzyme-1 (BACE1), the rate-limiting enzyme for β-amyloid (Aβ) production, is elevated in Alzheimer’s disease (AD). Here, we show that energy deprivation induces phosphorylation of the translation initiation factor eIF2α eIF2α-P), which increases the translation of BACE1. Salubrinal, an inhibitor of eIF2α-P phosphatase PP1c, directly increases BACE1 and elevates Aβ production in primary neurons. Preventing eIF2α phosphorylation by transfection with constitutively active PP1c regulatory subunit, dominant negative eIF2α kinase PERK, or PERK inhibitor P58IPK blocks the energy deprivation-induced BACE1 increase. Furthermore, chronic treatment of aged Tg2576 mice with energy inhibitors increases levels of eIF2α-P, BACE1, Aβ, and amyloid plaques. Importantly, eIF2α-P and BACE1 are elevated in aggressive plaque-forming 5XFAD transgenic mice, and BACE1, eIF2α-P, and amyloid load are all correlated in humans with AD. These results strongly suggest that eIF2α phosphorylation increases BACE1 levels and causes Aβ overproduction, which could be an early, initiating molecular mechanism in sporadic AD.

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Metadata

Authors
O'Connor, T., Sadleir, K. R., Maus, E., Velliquette, R. A., Zhao, J., Cole, S. L., Eimer, W. A., Hitt, B., Bembinster, L. A., Lammich, S., Lichtenthaler, S. F., Hébert, S. S., De Strooper, B., Haass, C., Bennett, D. A., & Vassar, R.
Venue
Neuron
Publisher
Elsevier BV
Published
2008-12
Volume
60
Issue
6
Pages
988-1009
ISSN
0896-6273 (ISSN-L)
DOI
10.1016/j.neuron.2008.10.047
OpenAlex
W2088835723
Cited by
421
References
19
FWCI
11.86
Type
journal article
Language
en
Open access
bronze

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